Azabicyclic compounds and pharmaceutical compositions containing them

ABSTRACT

Compounds of the formula I ##STR1## wherein R 1  represents ##STR2## and the remainder of the variables are defined in the specification are useful in the treatment and/or prophylaxis of dementia in mammals.

This invention relates to compounds having pharmaceutical activity, to aprocess for their preparation and their use as pharmaceuticals.

EP-0338723 and EP-0392803 (published 17 Oct. 1990) disclose certainazabicyclic compounds which enhance acetylcholine function via an actionat muscarinic receptors.

A novel group of compounds has now been discovered which also enhanceacetylcholine function via an action at muscarinic receptors within thecentral nervous system and are therefore of potential use in thetreatment and/or prophylaxis of dementia in mammals.

According to the present invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof: ##STR3##wherein R₁ represents ##STR4## in which p represents 2 or 3;

R₂ is a group OR₄, where R₄ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, agroup OCOR₅ where R₅ is hydrogen or R₄, or a group NHR₆ or NR₇ R₈ whereR₆, R₇ and R₈ are independently C₁₋₂ alkyl; and

R₃ is hydrogen, chloro, fluoro, bromo, cyclopropyl, C₁₋₄ alkyl, C₁₋₃alkyl substituted by one, two or three halogen atoms, or R₃ is a group(CH₂)_(n) R₉ where R₉ is --CN, --OH, --OCH₃, --SH, --SCH₃, --C.tbd.CH or--CH═CH₂ and n is 0 or 1, with the proviso that when n is 0, R₉ is not--OH or --SH, or, when, R₂ is OCOR₅ or NHR₆, R₃ may not be hydrogen.

The term halogen includes bromine, chlorine, fluorine and iodine,preferably fluorine.

Compounds of formula (I) are capable of existing in a number ofstereoisomeric forms including geometric isomers such as syn and antiand enantiomers. The invention extends to each of these stereoisomericforms, and to mixtures thereof (including racemates). The differentstereoisomeric forms may be separated one from the other by the usualmethods, or any given isomer may be obtained by stereospecific orasymmetric synthesis.

The compounds of formula (I) can form acid addition salts with acids,such as the conventional pharmaceutically acceptable acids, for examplehydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,citric, lactic, mandelic, tartaric, oxalic and methanesulphonic.

The term pharmaceutically acceptable salt encompasses solvates andhydrates. Thus where compounds of formula (I) or pharmaceuticallyacceptable salts thereof form solvates or hydrates, these also form anaspect of the invention.

Preferably, p represents 2.

The groups R₄ and R₅ in R₂ are preferably selected from methyl, ethyl,allyl and propargyl. R₆, R₇ and R₈ are preferably methyl. Suitablevalues for R₂ include methoxy, ethoxy, allyloxy, propargyloxy, acetoxyand dimethylamino, preferably methoxy.

Suitable examples for R₃ include hydrogen, methyl, cyclopropyl, chloro,fluoro and bromo and when R₃ is a group (CH₂)_(n) R₉ and n is 0,suitable examples of R₉ include --CN, --OCH₃ or --C.tbd.CH. When n is 1,an example of R₉ is CN.

The invention also provides a process for the preparation of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, whichprocess comprises:

(a) reacting a compound of formula (II): ##STR5## with a compound offormula (III):

    R.sub.2 '--NH.sub.2                                        (III)

wherein R₁ ' represents R₁ or a group convertible thereto, R₂ 'represents R₂ or hydroxy, and R₃ ' represents R₃ or a group convertiblethereto, converting R₂ ' to R₂ when hydroxy, converting R₁ ' and R₃ 'when other than R₁ and R₃ to R₁ and R₃, wherein R₁, R₂ and R₃ are asdefined in formula (I), and thereafter optionally forming apharmaceutically acceptable salt;

(b) reacting a compound of formula (IV): ##STR6## with a compound offormula (V):

    M--R.sub.3 '                                               (V)

capable of generating an R₃ ' nucleophile wherein R₁ ' represents R₁ ora group convertible thereto, R₃ ' represents R₃ or a group convertiblethereto, converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁ andR₃, wherein R₁, R₂ and R₃ are as defined in formula (I), and thereafteroptionally forming a pharmaceutically acceptable salt;

(c) reacting a compound of formula (IVa) ##STR7## wherein R₁ ' and R₂are as defined in formula (IV), with a chlorinating, brominating orfluorinating agent, converting R₁ ' when other than R₁ to R₁, optionallyconverting R₃ when chloro or bromo to other R₃ wherein R₃ is as definedin formula (I), and thereafter optionally forming a pharmaceuticallyacceptable salt;

(d) the nitrosation of a compound of formula (IVb) or (IVc): ##STR8##wherein R₁ ' and R₃ ' are as defined in formula (II) and p is as definedin formula (I), and thereafter converting the resulting ═NOH group to═NR₂ wherein R₂ is as defined in formula (I), converting R₁ ' and R₃ 'when other than R₁ and R₃ to R₁ and R₃ and thereafter optionally forminga pharmaceutically acceptable salt; or

(e) reacting a compound of formula (IVd) ##STR9## wherein R₁ ' and R₃ 'represent R₁ and R₃ as defined in formula (I) or groups convertiblethereto, to convert the hydroxy group to R₂ as defined in formula (I),and thereafter converting R₁ ' and R₃ ' when other than R₁ and R₃ to R₁and R₃ and optionally forming a pharmaceutically acceptable salt.

It will be appreciated that compounds of formula (IV) are identical tocompounds of formula (I) in which R₁ ' is R₁ and R₃ is chloro or bromo,and as such are themselves part of the invention.

The reaction between the compounds of formulae (II) and (III) ispreferably carried out in a hydroxylic solvent such as methanol orethanol, at ambient temperature, or where appropriate, at elevatedtemperature.

Where R₂ in compounds of formula (I) is a group OR₄, NHR₆ or NR₇ R₈, acompound of formula (II) is conveniently reacted with a compound offormula (III) in which R₂ ' is R₂.

Where R₂ in compounds of formula (I) is a group OCOR₅, a compound offormula (II) may be reacted with the compound of formula (III) in whichR₂ ' is hydroxy, with subsequent acylation of the resulting oxime offormula (IVd) by treatment with a suitable acylating agent such as anacyl halide, for example acetyl chloride.

The reaction between compounds of formulae (IV) and (V) may be carriedout under standard conditions for the displacement of halogen by anucleophile.

Where R₃ in compounds of formula (I) is fluoro, the residue M issuitably caesium, the caesium fluoride reagent being supported oncalcium fluoride in dimethylformamide at elevated temperature for aprolonged period.

The nitrosation of the compound of formula (IVb) or (IVc) is preferablycarried out using t-butyl nitrite and a base such as sodium ethoxide or,more preferably, potassium t-butoxide, and R₃ ' is preferably anelectron withdrawing group other than halo, such as CN.

The resulting ═NOH group in the oxime of formula (IVd) may be convertedto ═NR₂ by conventional routes such as acylation as described above oralkylation with an alkylating agent such as methyltosylate or an alkylhalide for example methyl iodide. It will be appreciated that R₃ ' ispreferably other than halo, such as CN.

The product of the reaction of compounds of formulae (II) and (III) andformulae (IV) and (V) and the nitrosation of the compound of formula(IVb) or (IVc) is a compound of formula (IIa): ##STR10## wherein R₂ 'represents R₂ or hydroxy and R₁ ' and R₃ ' represent R₁ and R₃ or groupsconvertible thereto, and R₁, R₂ and R₃ are as defined in formula (I).

Intermediates of formula (IIa) wherein R₁ ' is not R₁ when R₂ ' and R₃ 'are R₂ and R₃, also form part of the invention.

It will be appreciated that the reaction of compounds of formula (IVa)with a chlorinating, brominating or fluorinating agent will yieldcompounds of formula (I) wherein R₃ is chloro, bromo or fluoro. Suitablechlorinating agents include phosphorus pentachloride which undergoesreaction in nitromethane at reduced temperature, for example 0° C., anddichlorotriphenylphosphine or carbon tetrachloride/triphenyl phosphinewhich undergoes reaction in acetonitrile at elevated temperature, forexample at the boiling point of the solvent. Suitable brominating agentsinclude dibromotriphenylphosphine or carbontetrabromide/triphenylphosphine which undergoes reaction in acetonitrileat elevated temperature, for example at the boiling point of thesolvent. Suitable fluorinating agents include diethylaminosulphurtrifluoride (DAST) which also undergoes reaction in acetonitrile atelevated temperature.

Conversion of the resulting R₃ halogen group when chloro or bromo toother R₃ groups may be effected by reaction variant (b) above.

Compounds of formula (II) and compounds of formulae (IV) and (IVa) maybe prepared from an intermediate compound of formula (VI): ##STR11## inwhich L is a leaving group such as chloro, bromo, C₁₋₄ alkoxy orN-methoxy-N-methylamino and R₁ ' is as defined in formula (II). Acompound of formula (VI) in which L is preferably chloro or bromo may bereacted with N,O-dimethylhydroxylamine and the resultingN-methoxy-N-methylcarboxamide derivative reacted with a compound offormula (V), suitably disobutylaluminium hydride or lithium aluminiumhydride or an organolithium such as methyl lithium or a Grignardreagent, to provide a compound of formula (II). Where R₃ is ethynyl, itis preferably protected in the compound of formula (V) which is suitablylithium (trimethylsilyl) acetylene. The trimethylsilyl protecting groupis preferably removed after reaction of the compounds of formulae (II)and (III) by treatment with aqueous sodium hydroxide.

Where R₃ is cyclopropyl, a compound of formula (VI) in which L ispreferably chloro or bromo may be treated withcyclopropyltrimethylsilane in the presence of aluminium trichloride indichloromethane.

Where R₃ is CH₂ CN, a compound of formula (VI) in which L is preferablyC₁₋₄ alkoxy or N-methoxy-N-methylamino may be treated with a suitableorganolithium or Grignard reagent, for example the reaction product ofacetonitrile and lithium diisopropylamide. It will be appreciated thatthe resulting compound of formula (II) will be in the form of thelithium enolate salt.

A compound of formula (VI) may alternatively be reacted with a compoundof formula (III) wherein R₂ ' is OR₄, in chloroform or acetonitrile or amixture as solvent, in the presence of a base such as pyridine ortriethylamine, and the resulting derivative of formula (IVa) treatedwith a chlorinating or brominating agent to provide a compound offormula (IV) in which R₂ is OR₄.

Novel compounds of formulae (II), (IV), (IVa), (IVb), (IVc), (IVd) and(VI) also form part of the invention.

In particular, the invention provides intermediates of formula (XIII):

    R.sub.1 '--Q                                               (XIII)

wherein R₁ ' is R₁ or a group convertible thereto and Q is selected from--COR₃ ', --CONHR₂, --CON(CH₃)OCH₃, --C(R₃ ')═NR₂ ' and --CH₂ --R₃ ',and R₁ ' and R₃ ' are R₁ and R₃ or groups convertible thereto and R₂ 'is R₂ or hydroxy, provided that R₁ ' is not R₁ when Q is --C(R₃ ')═NR₂ 'and R₂ ' and R₃ ' are R₂ and R₃, including salts thereof.

Compounds of formula (VI) and (IVb) and certain compounds of formula(II) may conveniently be prepared by cyclising a compound of formula(VII): ##STR12## where F is one and G is the other of --(CH₂)_(p) -- and--CH₂ -- or groups convertible thereto, Y¹ is CN or COL₁ and Y² is--(CH₂)₂ W where W is CN or COL₁ and L₁ is a leaving group, andthereafter, or as necessary and in any appropriate order, reducing thecarbonyl group in the cyclisation product to hydroxy and dehydrating theresulting alcohol, converting W to COL, COR₃ ' or CH₂ R₃ ' andconverting F and G to --(CH₂)_(p) -- and --CH₂ -- as appropriate.

Examples of leaving groups L₁ include C₁₋₄ alkoxy such as ethoxy.

In the cyclisation process, where Y¹ and Y² both contain carboxy estergroups, the cyclisation is a Dieckmann reaction which is catalysed by abase such as potassium t-butoxide at elevated temperature in a solventsuch as toluene and the product is a β-keto ester.

In the cyclisation process, where Y¹ and Y² both contain cyano groupsthe cyclisation is a Thorpe reaction which is catalysed by a base suchas potassium t-butoxide at elevated temperature in a solvent such astoluene and the product, after acid work up, is a β-keto nitrile.

The β-keto ester or nitrile cyclisation product may be reduced byconventional procedures with an alkali metal borohydride such as sodiumborohydride in a lower alcohol such as ethanol, to yield the 4-hydroxycompound usually as a mixture of axial and equatorial alcohols. Themixture may be dehydrated under conventional conditions for theformation of an unsaturated system, such as under strongly acidicconditions e.g. with concentrated sulphuric acid and glacial aceticacid, at elevated temperature such as the boiling point of the solvent,the acid reagent optionally acting as the solvent. More preferably thedehydration may be carried out by prior conversion to the mesylate. Theaxial and equatorial alcohols may be separated by conventionalchromatography, and converted into the mesylates under standardconditions, such as methane sulphonyl chloride in the presence of drypyridine which may function as the solvent. Under these conditions theaxial alcohol undergoes dehydration in situ. The mesylate of theequatorial alcohol can be converted into an axial ester derivative, suchas the acetate, with sodium acetate in a suitable solvent such asN,N-dimethylformamide, at elevated temperature. The intermediate is notisolated and undergoes elimination to give the required product.Alternatively the mixture of axial and equatorial alcohols may besubjected sequentially to the conditions required for the dehydration ofeach isomer. It will be appreciated that the reduction and dehydrationsteps may be carried out before or after the conversion of W to the--C(R₃)═NR₂ group.

The 4-keto and 4-hydroxy azabicycloalkane moieties are thereforeexamples of R₁ ' convertible to R₁.

The conversion of W to COL, COR₃ ' or CH₂ R₃ ' may be carried outconventionally.

A carboxy group may be obtained by conventional de-esterification of a Walkoxycarbonyl or cyano group. A carboxy group may be treated withthionyl chloride at elevated temperature to give the chlorocarbonylgroup, COCl or with thionyl bromide to give the bromocarbonyl group,COBr.

An R₃ 'CO-- group where R₃ ' is C₁₋₄ alkyl may be obtained from a Wcyano group by treatment with the appropriate alkyl lithium in ether atdepressed temperature, or by treatment of a LiOOC group with an alkyllithium, the LiOOC group being obtained by hydrolysis of a Walkoxycarbonyl group with lithium hydroxide in water Alternatively, anR₃ 'CO-- group where R₃ ' is C₁₋₄ alkyl may be obtained by reaction of achlorocarbonyl group with N,O-dimethylhydroxylamine and treatment withan alkyl lithium.

A W cyano or carboxylic acid derivative group such as alkoxycarbonyl orN-methoxy-N-methylamido may be converted to --CHO (i.e. R₃ 'CO-- whereR₃ ' is hydrogen) by controlled reduction using a suitable reducingagent such as diisobutylaluminium hydride or lithium aluminium hydridein an inert solvent such as toluene or tetrahydrofuran at lowtemperature. The formyl group may then be converted to CH₂ CN bytreatment with p-toluenesulphonylmethyl isocyanide under basicconditions at depressed temperature.

Compounds of formula (IVc) may be prepared as described in EP 0414394,for example by reacting a compound of formula (VIIa): ##STR13## with aphosphorus ylide of formula (X) or (XI): ##STR14## in which Ra, Rb andRc are independently C₁₋₆ alkyl, aryl or aralkyl and Z is an electronwithdrawing group such as CN or a carboxylic acid, or ester or amidederivative thereof to give a compound of formula (XII): ##STR15## inwhich Z is as defined for formulae (X) and (XI); and thereafter wherenecessary, converting Z to R₃ '.

The reaction of a compound of formula (VIIa) with a phosphorus ylide offormula (X) or (XI) which is equivalent to the conversion of a ketone toan olefin is known as a Wittig Reaction and may be carried out underconditions generally used for such reactions. Preferably a compound offormula (VIIa) is reacted with a compound of formula (XI) in which Raand Rb are each C₁₋₆ alkyl, for example ethyl, and Z is cyano.

Where the Z group is a carboxy derivative such as an alkoxycarbonylgroup, it may be converted to a cyano group by conventional methods.

However, as stated above, Z is preferably cyano and no conversion isnecessary.

Intermediates of formulae (VII) and (VIIa) are known compounds (e.g. asdescribed in Thill et al., J. Org. Chem., 1968, 33, 4376) or may beprepared analogously.

For example, a compound of formula (VIII): ##STR16## where Y¹, F and Gare as defined in formula (VII) and R₁₀ is hydrogen or an N-protectinggroup, may be deprotected if necessary by hydrogenation over palladiumon carbon, or preferably using Pd/C in the presence of ammonium formate,followed by reaction with ethyl acrylate in ethanol at elevatedtemperature.

Compounds of formula (VIII) are known compounds or may be prepared byanalogous methods to those for preparing known compounds. The compoundof formula (VIII) where F is --(CH₂)₂ --, G is --CH₂ -- and R₁₀ isbenzyl may be prepared by the cyclisation of di-C₁₋₄ alkyl itaconate inthe appropriate alkanol with benzylamine at elevated temperature,followed by reduction of the resulting oxo group at the 2-position ofthe pyrrolidine ring with BH₃ in tetrahydrofuran, at ambient to elevatedtemperature.

Alternatively, and preferably, a dipolar cycloaddition of a C₁₋₄ alkylacrylate with a compound of formula (IX): ##STR17## in which R₁₀ is anN-protecting group in the presence of a catalytic amount oftrifluoroacetic acid, yields a compound of formula (VIII) directly.

Compounds of formula (IX) may be prepared conventionally by the reactionof the primary amine R₁₀ NH₂ successively withchloromethyltrimethylsilane then formaldehyde, methanol and anhydrouspotassium carbonate.

Compounds of formula (III) are known compounds or may be prepared byanalogous methods to those for preparing known compounds. Certaincompounds of formula (III) are commercially available.

The different stereoisomeric forms of compounds of formula (I) may beseparated one from the other by the usual methods, for example usingchromatographic methods. Enantiomers may be separated using chiralresolving agents or chiral chromatography, or any given isomer may beobtained by stereospecific or asymmetric synthesis.

Pharmaceutically acceptable salts of the compounds of formula (I) may beformed conventionally by reaction with the appropriate acid such asdescribed above under formula (I).

The compounds of the present invention enhance acetylcholine functionvia an action at muscarinic receptors within the central nervous systemand are therefore of potential use in the treatment and/or prophylaxisof dementia.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, or hydrogenated edible fats; emulsifying agents, forexample lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles(which may include edible oils), for example almond oil, fractionatedcoconut oil, oily esters such as esters of glycerine, propylene glycol,or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouringor colouring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration.

The invention also provides a method of treatment and/or prophylaxis ofdementia in mammals including humans, which comprises administering tothe sufferer an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

The dose of the compound used in the treatment of such disorders willvary in the usual way with the seriousness of the disorders, the weightof the sufferer, and the relative efficacy of the compound. However, asa general guide suitable unit doses may be 0.05 to 100 mg, for example0.2 to 50 mg and such unit doses may be administered more than once aday, for example two or three times a day, so that the total dailydosage is in the range of about 0.01 to 5 mg/kg and such therapy mayextend for a number of weeks or months.

When administered in accordance with the invention no unacceptabletoxicological effects are expected for the compounds of the invention.

In a further aspect the invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof for use as an activetherapeutic substance.

The invention further provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use in the treatmentand/or prophylaxis of dementia.

In another aspect the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment and/or prophylaxis ofdementia.

The following examples illustrate the invention and the followingdescriptions illustrate the preparation of intermediates thereto.

DESCRIPTION 1 (±) Ethyl N-benzyl-3-pyrrolidinylcarboxylate (D1)

To a stirred solution of ethyl acrylate (141 g, 1.41 mole) andN-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (Compound D17of EP 0363085, 435 g, containing approximately 75% of D17, 1.4 moles) indichloromethane (2.5L) at -5° C. was added trifluoroacetic acid (16.1 g,0.14 mole) in dichloromethane (100 ml) ensuring that the temperature didnot rise above 0° C. This mixture was then transferred by cannula tostirred, refluxing dichloromethane (50 ml) over 40 minutes at such arate as to maintain gentle reflux. The reaction mixture was thenrefluxed for a further 1h before cooling to room temperature. It wasthen washed with saturated aqueous potassium carbonate, dried (Na₂ SO₄),and concentrated in vacuo to a gum which was distilled to afford thetitle compound (D1) as a clear oil (286 g, 88%) b.p. 120°-150° C. at 4mmHg.

¹ NMR (CDCl₃) δ: 1.23 (3H, t, J=7 Hz), 2.01-2.12 (2H, m), 2.34-2.75 (3H,m), 2.83-3.07 (2H, m), 3.59 (2H, s), 4.10 (2H, q, J=7 Hz ), 7.16-7.33(5H, m).

DESCRIPTION 2 (±) EthylN-(2-ethoxycarbonylethyl)-3-pyrrolidinylcarboxylate (D2)

A solution of (±) ethyl N-benzyl-3-pyrrolidinyl carboxylate (D1) (100 g,0.43 mole) in ethanol (800 ml) was treated with ammonium formate (135.32g, 2.15 mole) and 10% Pd on carbon (25 g) then heated at 70° C. for 2h.After 1h a further addition of 10% Pd on carbon (10 g) was made. Thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo. The residue was partitioned between chloroformand saturated aqueous potassium carbonate solution. The organic phasewas separated, dried (Na₂ SO₄), and concentrated in vacuo. The residuewas dissolved in ethanol (500 ml), treated with ethyl acrylate (51.56 g,0.52 mole) then heated under reflux for 1h. The reaction mixture wasconcentrated in vacuo, treated with saturated aqueous potassiumcarbonate, then extracted into chloroform. The combined organic extractswere dried (Na₂ SO₄), concentrated in vacuo and the residue distilled toafford the title compound (D2) as an oil (60.53 g, 58%), b.p. 135°-145°C. at 4 mmHg.

¹ H NMR (CDCl₃) δ: 1.28 (6H, t, J=7 Hz), 2.03-2.14 (2H, m), 2.47-2.57(3H, m), 2.61-2.86 (4H, m), 2.87-3.12 (2H, m), 4.15 (4H, q, J=7 Hz).

DESCRIPTION 3 (±)exo-Ethyl-4-oxo-1-azabicyclo[3.2.1]oct-3-yl-carboxylate (D3)

A solution of (±) ethylN-(2-ethoxycarbonylethyl)-3-pyrrolidinylcarboxylate (D2) (5.77 g, 25.2mmole) in dry toluene (10 ml) was added dropwise over 1h to a solutionof potassium t-butoxide (7.57 g, 55.4 mmoles) in dry toluene (50 ml) atreflux, under nitrogen. After a further 2h at reflux, the reactionmixture was cooled to -5° C. and then quenched by the addition of aceticacid (3.33 ml, 55.4 mmole) keeping the temperature below 0° C. Themixture was filtered, and the filtrate concentrated in vacuo to affordthe title compound (D3) as a white solid (2.6 g, 47%) which was usedwithout further purification.

DESCRIPTION 4 AND 5 cis- and trans-exo-Ethyl4-hydroxy-1-azabicyclo[3.2.1]-oct-3-ylcarboxylate (D4 and D5)

A solution of (±) exo-ethyl-4-oxo-1-azabicyclo[3.2.1]oct-3-ylcarboxylate(D3) (17.71 g, 90 mmole) in dry ethanol (100 ml) was cooled in ice undernitrogen and treated with sodium borohydride (1.7 g, 45 mmole)portionwise over 15 min. The reaction mixture was allowed to warm up toroom temperature over 1h. It was then concentrated in vacuo, treatedwith saturated aqueous potassium carbonate (20 ml) and extracted intochloroform (3×15 ml). The extracts were dried (Na₂ SO₄) thenconcentrated in vacuo and the residue chromatographed on basic aluminain a gradient of 0-3% methanol in chloroform to afford, in order ofelution, the cis isomer (D4) as a clear oil (4.73 g, 26%) and the isomer(D5) as an off-white solid (3.81, 21%).

D4

¹ H NMR (CDCl₃) δ: 1.26 (3H, t, J=7 Hz), 1.57-1.73 (1H, m), 1.85-2.01(1H, m), 2.27-2.53 (2H, m), 2.59-2.82 (4H, m), 2.87-3.09 (2H, m),3.97-4.05 (1H, m), 4.16 (2H, q, J=7 Hz).

¹³ C NMR (CDCl₃) δ: 14.54, 25.48, 40.70, 46.01, 51.95, 55.87, 58.66,61.25, 71.68, 174.20

D5

¹ H NMR (CDCl₃) δ: 1.26 (3H, t, J=7 Hz), 1.45-1.60 (1H, m), 1.72-1.86(1H, m), 2.28-2.41 (2H, m), 2.61-2.71 (1H, m), 2.78-3.02 (3H, m),3.09-3.18 (1H, m), 3.37-3.45 (1H, m), 4.06-4.20 (3H, m)

¹³ C NMR (CDCl₃) δ: 14.19, 27.72, 39.81, 39.84, 50.29, 52.96, 53.32,60.91, 68.98, 174.31

DESCRIPTION 6 (±) Ethyl 1-azabicyclo[3.2.1]oct-3-en-3-ylcarboylate (D6)

Method (a)

A solution of (±) cis-exo-ethyl4-hydroxy-1-azabicyclo[3.2.1]oct-3-ylcarboxylate (D4), (2 g, 10.1 mmole)in dry pyridine (10 ml) at 0° C. was treated dropwise withmethanesulphonyl chloride (3.45 g, 30.2 mmole) over fifteen minutes. Thereaction mixture was allowed to warm to room temperature over 3h,concentrated in vacuo, then treated with saturated aqueous potassiumcarbonate (100 ml), and extracted into chloroform (3×100 ml). Thecombined organic extracts were dried (Na₂ SO₄) and evaporated to give aresidue which was chromatographed on neutral alumina in a gradient of0-2% methanol in chloroform to afford the title compound (D6) as a gum(1 g, 53%).

¹ H NMR (CDCl₃) δ: 1.26 (3H, t, J=7 Hz), 1.80-2.12 (2H, m), 2.57-3.01(4H, m), 3.06-3.22 (1H, m), 3.35 (1H, d, J=17 Hz), 3.93 (1H, d, J=17Hz), 4.16 (2H, q, J=7 Hz), 7.19-7.28 (1H, m).

¹³ C NMR (CDCl₃) δ: 14.25, 33.60, 36.53, 54.52, 55.85, 58.32, 60.25,126.96, 145.60, 166.35

Method (b)

A solution of (±) trans-exo-ethyl4-hydroxy-1-azabicyclo[3.2.1]oct-3-ylcarboxylate (D5), (3.9 g, 0.0196mole) in dry pyridine (50 ml) under nitrogen was treated dropwise withmethanesulphonyl chloride (3.8 ml, 0.049 mole) over a period of 0.75hwith ice cooling. The mixture was stirred at room temperature for 3h,and then concentrated in vacuo. After co-distillation with dry tolueneto remove volatiles, the residue was dried further under high vacuum.The resulting gum was dissolved in dry N,N-dimethylformamide (100 ml),treated with anhydrous sodium acetate (8.2 g, 0.1 mole) and heated to100° C. over a period of 1h. The reaction was maintained at thistemperature for a further 0.75h, and then concentrated in vacuo. Afterco-distillation with toluene, the residue was treated with a saturatedsolution of potassium carbonate (25 ml) and extracted into chloroform(4×25 ml). The combined organic extracts were dried (Na₂ SO₄) andconcentrated in vacuo to give a crude oil. Purification on silica gel ina gradient of 2-6% methanol in chloroform afforded the title compound(D6) (1.9 g, 54%).

Method (c)

A 3:1 mixture of the cis and trans isomers (D4) and (D5) (9.89 g, 0.050mole) subjected to the reaction conditions described in Method (b), gavethe title compound (D6) (6.23 g, 71%).

DESCRIPTION 7 (±) 1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboxamide(D7)

A solution of (±) ethyl 1-azabicyclo[3.2.1]-oct-3-en-3-ylcarboxylate(D6) (0.52 g, 2.9 mmole) in ethanol (6 ml) was treated with 85%potassium hydroxide (0.38 g, 5.7 mmole) then heated under reflux for 9h.The reaction mixture was concentrated in vacuo, treated with 5Nhydrochloric acid (1.72 ml, 8.6 mole) then concentrated in vacuo andco-distilled with toluene to remove the last traces of water. Theresidue was treated with thionyl chloride (10 ml), heated at refluxunder nitrogen for 25 minutes then concentrated in vacuo andco-distilled with toluene to afford the crude acid chloride. A solutionof this material in a mixture of dry acetonitrile (12 ml) and drychloroform (10 ml), under nitrogen, was treated with methoxylaminehydrochloride (0.48 g, 5.8 mmole) then cooled to -30° C. and treated ina single rapid addition with pyridine (1.09 g, 29 mmole) in acetonitrile(2 ml). The reaction mixture was allowed to warm to room temperature andstirred at room temperature overnight. It was then treated withsaturated aqueous potassium carbonate (25 ml), the organic phase wasseparated, and the aqueous phase extracted with chloroform (8×25 ml).The combined organic extracts were dried (Na₂ SO₄), concentrated invacuo and the residue chromatographed on neutral alumina in a gradientof 0-10% methanol in chloroform to afford the title compound (D7) as abrown gum (0.17 g, 34%).

¹ H NMR (CDCl₃) δ: 1.82-2.12 (2H, m), 2.57-3.02 (4H, m), 3.11-3.26 (1H,m), 3.37 (1H, d, J=17 Hz), 3.68 (3H, s), 3.94 (1H, d, J=17 Hz), 6.84(1H, d, J=7 Hz).

DESCRIPTION 8 (±)1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-N-methylcarboxamide (D8)

A solution of (±)ethyl 1-azabicyclo[3.2.1]oct-3-en-3-yl carboxylate (D6)(1.9 g, 10.5 mmole) in 5M hydrochloric acid (25 ml) was heated at 100°C. for 7h. The reaction was concentrated in vacuo and dried byco-distillation with toluene. The resulting brown solid (2.0 g) wassuspended in thionyl chloride (20 ml) and heated under reflux until allthe acid had dissolved (approx. 10 minutes). After concentrating thereaction in vacuo, residual traces of volatile material were removed byco-distillation with toluene, and the residue was finally dried underhigh vacuum. A suspension of the acid chloride in absolute chloroform(50 ml) was treated with N,O-dimethylhydroxylamine hydrochloride (1.13g, 11.5 mmole) and cooled in an ice-salt bath. Pyridine (4.2 ml, 5.3mmole) was added dropwise with good stirring over a period of 1h. Thereaction was allowed to warm to room temperature and stirred overnight.After cooling in an ice bath, the reaction was quenched with a saturatedaqueous solution of potassium carbonate (25 ml). The aqueous layer wasextracted with chloroform (3×25 ml), and the combined organic extractswere dried (Na₂ SO₄) and concentrated in vacuo to give an oil which wasextracted into ether, and then distilled on a kugelrohr (175° C./0.2mmHg) to afford the title compound (D8) as a pale yellow oil (1.1 g,54%) which solidified on cooling.

¹ H NMR (CDCl₃) δ: 1.9 (1H, m), 2.1 (1H, m), 2.55 (1H, m), 2.68 (1H, m),2.9 (1H, m), 3.05 (1H, m), 3.15 (1H, m), 3.20 (3H, s), 3.32 (1H, d,J=17.5 Hz), 3.64 (3H, s), 4.02 (1H, d, J=17.5 Hz), 6.64 (1H, d, J=7 Hz).

DESCRIPTION 9 (±)1-Azabicyclo[3.2.1]oct-3-en-3-ylcarboxaldehyde (D9)

A solution of(±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-N-methylcarboxamide (D8)(0.25 g, 1.28 mmol) in dry tetrahydrofuran (10 ml) was cooled to -70° C.under an atmosphere of nitrogen then treated with 1.5Mdiisobutylaluminium hydride in toluene (1.1 ml, 1.66 mmole) over 5minutes. The reaction was allowed to warm up to 0° C. over 1h, then itwas cooled to -60° C. and poured into vigorously stirred 5N hydrochloricacid (25 ml) which had been cooled to 0° C. The tetrahydrofuran wasremoved in vacuo, the aqueous solution was saturated with potassiumcarbonate and Rochelle salt, then extracted into chloroform (3×30 ml).The combined organic extracts were dried (Na₂ SO₄), concentrated invacuo and the residue distilled to afford the title compound (D9) as aclear oil (128 mg, 73%), b.p. 160° C./1 mmHg (kugelrohr apparatus).

¹ H NMR (CDCl₃) δ: 1.89-2.15 (2H, m), 2.67-3.98 (4H, m), 3.09-3.20 (1H,m), 3.32 (1H, d, J=17 Hz), 3.87 (1H, d, J=17 Hz), 7.11-7.19 (1H, m),9.33 (1H, s).

¹³ C NMR (CDCl₃) δ: 34.45, 36.62, 54.56, 56.12, 56.26, 137.34, 155.86,193.12.

DESCRIPTION 10 (±)3-Acetyl-1-azabicyclo[3.2.1]oct-3-ene (D10)

A solution of(±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-N-methylcarboxamide (D8)(0.40 g, 2.0 mmole) in dry tetrahydrofuran (20 ml) was cooled to -70°C., under a nitrogen atmosphere, and treated dropwise over 15 minuteswith methyllithium (1.47 ml of a 1.5 m solution in diethyl ether as thecomplex with lithium bromide, 2.2 mmole). The temperature was maintainedat -70° C. for 30 minutes, and then allowed to warm to 0° C. over 1.75h.The reaction was cooled to -20° C. and poured into a 1M solution oforthophosphoric acid (20 ml) cooled below 0° C. The organic layer wasseparated, and the aqueous phase was saturated with potassium carbonate,and extracted exhaustively with chloroform. The combined organicextracts were dried (Na₂ SO₄) and concentrated in vacuo to give a paleyellow oil (0.33 g) which was distilled in a kugelrohr at 150° C./0.1mmHg to give the title compound (D10) as a colourless liquid (0.28 g,93%).

¹ H NMR (CDCl₃) δ: 1.9-2.23 (2H, m), 2.2 (3H, s), 2.6-3.2 (5H, m), 3.35(1H, d, J=18 Hz), 3.88 (1H, d, J=18 Hz), 7.18 (1H, d, J=7 Hz).

DESCRIPTION 11 (±) 3-Cyanomethylene-1-azabicyclo[3.2.1]octane (D11).

Diethyl cyanomethylphosphonate (5.67 g, 0.032 mole) in THF (75 ml) wasadded over 10 minutes to a stirred solution of potassium tert-butoxide(3.60 g, 0.032 mole) in THF (75 ml) at 0° C. The reaction mixture wasthen cooled to -20° C. before dropwise addition of1-azabicyclo[3.2.11octan-3-one* (3.64 g, 0.029 mole) in THF (50 ml) over15 minutes. The mixture was allowed to warm to room temperature, stirredfor 1h, and then poured into 20% aqueous potassium carbonate (150 ml)and extracted with ethyl acetate (3×200 ml). The combined organicextracts were dried (Na₂ SO₄) and evaporated to give the title compound(D11) as a 6:5 mixture of E and Z isomers (3.88 g, 90%). The isomerscould be separated chromatographically on silica using 3%methanol/chloroform as eluant to give in order of elution the Z-isomerand the E-isomer as oils.

Z-isomer

¹ H NMR (CDCl₃) δ: 1.59 (1H, m), 1.77 (1H, m), 2.30 (1H, m), 2.48-3.06(6H, m), 3.50 (1H, d, J=15 Hz), 3.81 (1H, d, J=15 Hz), 5.16 (1H, d).

¹³ C NMR (CDCl₃) δ: 29.97, 36.12, 41.71, 52.39, 59.78, 59.96, 96.47,115.78, 165.00.

E-isomer

¹ H NMR (CDCl₃) δ: 1.61 (1H, m), 1.28 (1H, m), 2.48-2.60 (2H, m),2.68-2.94 (4H, m), 3.03 (1H, d, J=11 Hz), 3.27 (1H, d, J=15 Hz), 3.59(1H, d, J=15 Hz), 5.22 (1H, s).

¹³ C NMR (CDCl₃) δ: 30.05, 35.88, 39.16, 52.24, 59.76, 62.44, 96.48,115.94, 164.79.

EXAMPLE 1 (±) 1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboximidoylbromide (E1)

A solution of (±) 1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboxamide(D7) (690 mg, 3.79 mmole) in a mixture of dry ether (45 ml) and methanol(5 ml) was treated with excess hydrogen bromide (1 g) while cooled inice. The solution was concentrated in vacuo then codistilled withacetonitrile to remove the last traces of methanol. A solution of theresidue in dry acetonitrile (100 ml) was treated with carbontetrabromide (1.38 g, 4.17 mmole) then heated to reflux under nitrogen.It was then treated with triphenylphosphine (1.09 g, 4.17 mmole) andheated under reflux for 5h. Further additions of carbon tetrabromide(1.38 g, 4.17 mmole) and triphenylphosphine (1.09 g, 4.17 mmole) weremade over this period. The reaction mixture was concentrated in vacuo,treated with saturated aqueous potassium carbonate (20 ml) thenextracted into chloroform (25 ml×3). The combined organic extracts weredried (Na₂ SO₄) and evaporated to give a residue which waschromatographed on silica in a gradient of 0-7% methanol in chloroformto afford the title compound (E1) as an off-white solid (240 mg, 26%).

¹ H NMR (CDCl₃) δ: 1.76-2.03 (3H, m), 3.58-2.66 (2H, m), 2.69-2.81 (1H,m) 2.86-2.95 (1H, m), 3.07-3.19 (1H, m) 3.38 (1H, d, J=17 Hz), 3.92 (1H,d, J=17 Hz), 3.93 (3H, s), 6.79 (1, d, J=7 Hz).

EXAMPLE 2 (±) 1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboximidoylchloride oxalate salt (E2)

A refluxing solution of (±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboxamide (D7) (80 mg, 0.43mmole) and carbon tetrachloride (125 mg, 0.82 mmole) in dry acetonitrile(15 ml), under nitrogen, was treated with triphenylphosphine (121 mg,0.45 mmole) then heated under reflux for 7 min. The reaction mixture wasconcentrated in vacuo and the residue chromatographed on silica in agradient of 0-4% methanol in chloroform to afford the imidoyl chlorideas a white solid (34 mg, 39%) which was converted to the oxalate salt(E2) m.p. 172° C. (decomp.) (from methanol-ether).

¹ H NMR (d₆ -DMSO) δ: 2.01-2.27 (2H, m), 2.98-3.41 (4H, m), 3.48-3.67(1H, m), 3.89 (1H, d, J=17 Hz), 3.95 (3H, s), 4.26 (1H, d, J=17 Hz),6.96 (1H, d, J=7 Hz).

¹³ C NMR (d₆ -DMSO) δ: 32.87, 33.14, 52.49, 54.18, 55.18, 63.15, 123.75,134.49, 137.98.

Analysis: C₁₁ H₁₅ N₂ O₅ Cl requires C: 45.45; H: 5.11; N: 9.64 found C:45.54; H: 5.11; N: 9.33

EXAMPLE 3 (±) 1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxcarboximidoylfluoride oxalate salt (E3) Method (i) (reaction variant (c))

(±) 1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboxamide (D7) (80 mg,0.44 mmole) was converted to the hydrofluoride salt by the addition ofhydrogen fluoride-pyridine (Aldrich). The salt was dissolved inrefluxing acetonitrile (10 ml), diethylaminosulphur- trifluoride (DAST)(74 mg, 0.46 mmole) in acetonitrile (1 ml) was added in a single portionthen the reaction mixture was heated under reflux for 30 seconds. It wasthen concentrated in vacuo, treated with saturated aqueous potassiumcarbonate (50 ml) and extracted into chloroform (3×75 ml). The combinedorganic extracted were dried (Na₂ SO₄), concentrated in vacuo and theresidue chromatographed on silica in a gradient of 0-4% methanol inchloroform. This afforded the imidoyl fluoride as a white solid (12 mg,15%).

Method (ii) (reaction variant (b))

A solution of (±)1-Azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboximidoyl bromide (E1, 0.1g, 0.4 mmole) in dry N,N-dimethylformamide (7 ml) was treated withcesium fluoride supported on calcium fluoride (4 g)* then heated at 140°C. under nitrogen for 4 days. The reaction mixture was filtered, thesolid washed with more N,N-dimethylformamide and the filtrateconcentrated in vacuo. It was then treated with saturated aqueouspotassium carbonate (50 ml) then extracted into chloroform (3×75 ml).The combined organic extracts were dried (Na₂ SO₄) and then concentratedin vacuo and the residue chromatographed on silica in a gradient of 0-3%methanol in chloroform to afford the imidoyl fluoride contaminated withabout 25% (E1) (10 mg, 13%). This was combined with the materialproduced using method (a) and converted to the oxalate salt which wasrecrystallised from methanol/ether to give the title compound (E3) whichcontained about 9% (E1).

¹ H NMR (d₆ -DMSO) δ: 2.12-2.21 (2H, m), 3.08-3.73 (SH, m), 3.75 (1H, d,J=16 Hz), 3.90 (3H, s), 4.16 (1H, d, J=16 Hz), 6.92 (1H, d, J=7 Hz ).

¹³ C NMR (d₆ -DMSO) δ: 32.74, 32.98, 52.67, 53.62, 54.25, 62.97, 118.12(d, ² J_(CF) =29 Hz), 136.50, 147.40 (d, ¹ J_(CF) =320 Hz).

MS Calculated mass for C₉ H₁₃ ON₂ F=184.1014 Observed mass=184.1011

Method (iii) (reaction variant (c))

Diethylaminosulphurtrifluoride (DAST) (1.58 g, 9.80 mmol) inacetonitrile (5 ml) was added in a single portion to(±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxycarboxamide (D7) (1.7 g,9.34 mmol) in acetonitrile (80 ml) at reflux. The reaction mixture wasthen immediately poured into saturated aqueous potassium carbonate (75ml) and extracted with chloroform (3×100 ml). The combined organicextracts were dried (Na₂ SO₄) and evaporated to a gum which waschromatographed on silica using 2% methanol/chloroform to give theimidoyl fluoride (0.39 g, 23%) as a crystallising oil. A portion of thismaterial was converted to the oxalate salt to give the title compound(E3) as a white crystalline solid mpt 153°-155° C. (decomp.).

Analysis C₉ H₁₃ N₂ OF.C₂ H₂ O₄ requires C:48.18; H:5.51; N;10.21 foundC:48.10; H:5.53; N:10.05.

EXAMPLE 4 (±)syn-1-Azabicyclo[3.2.1]oct-3-en-3-ylcarboxaldehyde-O-methyloximehydrochloride salt (E4)

A solution of (±)1-azabicyclo[3.2.1]oct-3-en-3-ylcarboxaldehyde (D9)(108 mg, 0.79 mmole) in dry methanol (7 ml) was treated withmethoxylamine hydrochloride (73 mg, 0.87 mmole) and stirred for 17h atroom temperature, under nitrogen. The reaction mixture was concentratedin vacuo, treated with saturated aqueous potassium carbonate (25 ml)then extracted into chloroform (3×30 ml). The combined organic extractswere dried (Na₂ SO₄), concentrated in vacuo and the residue waschromatographed on silica eluting with 5% methanol in chloroform. Thisafforded the aldoxime ether (76 mg, 58%) which was converted into thehydrochloride salt and recrystallised from methanol/diethyl ether toafford the title compound (E4) as a white crystalline solid m.p. 214° C.(decomp.).

¹ H NMR (d₆ -DMSO) δ: 2.10-2.35 (2H, m), 3.25-3.49 (4H, m), 3.61-3.77(1H, m), 3.89 (3H, s), 3.91 (1H, d, J=17 Hz), 4.30 (1H, d, J=17 Hz),6.67-6.74 (1H, m), 8.94 (1H, s).

¹³ C NMR (d₆ -DMSO) δ: 32.97, 33.41, 52.72, 54.34, 54.66, 61.94, 124.71,138.48, 148.25.

EXAMPLE 5 (±)trans 3-Acetyl-1-azabicyclo[3.2.1]oct-3-ene-O-methyloximehydrochloride salt (E5)

A solution of (±)3-acetyl-1-azabicyclo[3.2.1]oct-3-ene (D10) (0.27 g,1.79 mmole) in methanol (15 ml) was treated with methoxylaminehydrochloride (0.16 g, 1.96 mmole). After stirring overnight at roomtemperature, the reaction was concentrated in vacuo and treated with asaturated aqueous solution of potassium carbonate (10 ml). The mixturewas extracted with chloroform (4×10 ml) and the organic layers weredried (Na₂ SO₄) and concentrated to give a crude oil which was purifiedon a silica gel column using a graded eluant of 5-15% methanol inchloroform. Pooling of pure fractions containing the major fasterrunning component afforded the required oxime ether as an oil (0.19 g,59%) which was converted into the title hydrochloride salt (E5) m.p.241°-243° C. (from methanol-ether).

¹ H NMR (d₆ -DMSO) δ: 1.95 (3H, s), 2.1-2.4 (2H, m), 3.1-3.8 (6H, m),4.0 (3H, s), 4.28 (1H, d, J=16 Hz), 6.78 (1H, d, J=7 Hz).

¹³ C NMR (d₆ -DMSO) δ: 9.79, 32.65, 32.98, 52.25, 54.04, 54.83, 61.74,126.17, 133.38, 152.58.

Analysis: C₁₁ H₁₇ N₂ OCl requires C: 55.42; H: 7.91; N:12.93 found C:55.05; H:7.90; N: 12.73.

EXAMPLE 6(±)-α-(Methoxyimino)-α-(1-azabicyclo[3.2.1]oct-3-en-3-yl)acetonitrileoxalate salt (E6)

Potassium tert-butoxide (0.807 g, 7.19 mmol) was added portionwise to asolution of (±)3-cyanomethylene-1-azabicyclo[3.2.1]octane (D11) (0.967g, 6.53 mmol) in THF (40 ml) at -70° C. The resulting solution wasstirred for 0.5h at -60° C., then tert-butyl nitrite (0.87 ml ofapproximately 90% purity, 6.58 mmol) was added dropwise. The reactionmixture was allowed to warm to room temperature and stirred for 1.5h.Methyl p-toluenesulphonate (1.215 g, 6.53 mmol) in THF (10 ml) was addeddropwise and the resulting mixture was stirred at room temperatureovernight, then poured into saturated aqueous potassium carbonate (75ml) and extracted with ethyl acetate (3×100 ml). The combined organicextracts were dried (Na₂ SO₄) and evaporated to a gum which wassubjected to column chromatography on silica in a gradient of 1-5%methanol in chloroform to afford in order of elution(±)-α-(methoxyimino)-α-(1 -azabicyclo[3.2.1]oct-2-en-3-yl)acetonitrile(0.683 g, 55%) as a crystallising oil and(±)-α-(methoxyimino)-α-(1-azabicyclo[3.2.1]oct-3-en-3-yl)acetonitrile(0.194 g, 16%) as an oil. The latter compound was converted to theoxalate salt and recrystallised from acetone/methanol to give the titlecompound (E6) as a white crystalline solid m.p. 196°-198° C.

¹ H NMR (d₆ -DMSO) δ: 2.14 (2H, m), 3 07-3 36 (4H, m), 3.55 (1H, m) 3.85(1H, d, J=15 Hz), 4.06 (3H, s), 4.22 (1H, d, J=15 Hz), 6.86 (1H, d, J=5Hz).

¹³ C NMR (d₆ -DMSO) δ: 32.90, 33.37, 52.56, 54.16, 54.32, 64.41, 108.06,123.23, 130.24, 139.39.

Analysis C₁₀ H₁₃ N₃ O.C₂ H₂ O₄ requires C:51.24; H:5.38; N:14.94 foundC:51.24; H:5.38; N:14.88.

    ______________________________________                                        Compound   R.sub.2        R.sub.3                                                                              P                                            ______________________________________                                        E1         CH.sub.3 O     Br     2                                            E2         CH.sub.3 O     Cl     2                                            E3         CH.sub.3 O     F      2                                            E4         CH.sub.3 O     H      2                                            E5         CH.sub.3 O     CH.sub.3                                                                             2                                            E6         CH.sub.3 O     CN     2                                            ______________________________________                                    

BIOLOGICAL ACTIVITY Radio Ligand Binding

Cerebral cortex from Hooded Lister rats (Olac, UK) is homogenised in 2.5vols ice-cold 50 mM tris buffer pH 7.7 (at 25° C.). After centrifugationat 25,000×g at 4° C. for 15 min the pellet is resuspended in 2.5 volsbuffer and the wash repeated 3 times more. The final resuspension is in2.5 volumes and the homogenates are stored in 1 ml aliquots at -20° C.

Incubations (total volume 2 ml) are prepared using the above buffer withthe addition of 2 mM magnesium chloride in the 3H-Oxotremorine-M(3H-OXO-M) experiments. For 3H-Quinuclidinyl Benzilate (3H-QNB), 1 ml ofstored membranes is diluted to 30 ml and 0.1 ml mixed with test compoundand 0.27 nM (c. 25,000 cpm) 3H-QNB (Amersham International). For3H-OXO-M, 1 ml of membranes is diluted to 6 ml and 0.1 ml mixed withtest compound and 2 nM (c. 250,000 cpm) 3H-OXO-M (New England Nuclear).

Non-specific binding of 3H-QNB is defined using 1 μM Atropine sulphate(2 μM Atropine) and of 3H-OXO-M using 10 μM Oxotremorine. Non-specificbinding values typically are 5% and 25% of total binding, respectively.Incubations are carried out at 37° C. for 30 min and the samplesfiltered using Whatman GF/B filters. (In the 3H-OXO-M experiments thefilters are presoaked for 30 min in 0.05% polyethylenimine in water).Filters are washed with 3×4 ml ice-cold buffer. Radioactivity isassessed using a Packard BPLD scintillation counter, 3 ml Pico-Fluor 30(Packard) as scintillant.

This test provides an indication of the muscarinic binding activity ofthe test compound. The results are obtained as IC₅₀ values (i.e. theconcentration which inhibits binding of the ligand by 50%) for thedisplacement of the muscarinic agonist 3H-OXO-M and the muscarinicantagonist 3H-QNB. The ratio IC₅₀ (3H-QNB)/IC₅₀ (3H-OXO-M) gives anindication of the agonist character of the compound. Agonists typicallyexhibit a large ratio; antagonists typically exhibit a ratio near tounity. The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                      [3H]-OXO-M [3H]-QNB                                             Compound      IC.sub.50 (nM)                                                                           IC.sub.50 (nM)                                       ______________________________________                                        E2            100        1,100                                                E3 method     26           320                                                (iii)                                                                         E4            70         1,250                                                E5            175        1,450                                                E6            21           330                                                ______________________________________                                    

We claim:
 1. A compound of Formula (I) or a pharmaceutically acceptablesalt thereof: ##STR18## wherein R₁ represents ##STR19## in which prepresents 2 or 3; R₂ is a group OR₄, where R₄ is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, a group OCOR₅ where R₅ is hydrogen or R₄, or agroup NHR₆ or NR₇ R₈ where R₆, R₇ and R₈ are independently C₁₋₂ alkyl;andR₃ is chloro, fluoro, bromo, C₁₋₃ alkyl substituted by one, two orthree halogen atoms, or R₃ is --CN, --CH₂ CN, --OCH₃, --CH₂ SH, --SCH₃and --CH₂ SCH₃.
 2. A compound according to claim 1 wherein p is
 2. 3. Acompound according to claim 1 wherein R₄ and R₅ in R₂ are selected frommethyl, ethyl, allyl and propargyl and R₆, R₇ and R₈ in R₂ are methyl.4. A compound according to claim 1 wherein R₃ is selected from chloro,fluoro, bromo, CN, --OCH₃, and --CH₂ CN.
 5. A compound according toclaim 1 selected from the group consistingof:(±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-carboximidoyl bromide,(±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-carboximidoyl chloride,(±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-carboximidoyl flouride,and(±)-a-(methoxyimino)-a-(1-azabicyclo[3.2.1]oct-3-en-3-yl)acetonitrile.6. A pharmaceutical composition which comprises an effective amount of acompound according to claim 1 and a pharmaceutically acceptable carder.7. A method of treatment and/or prophylaxis of dementia in mammalsincluding humans, which comprises administering to the sufferer aneffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.